While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. A strategic planning process within DCEG led to a recommendation that the Division expand its activities in the area of intervention studies, a proposal which has been endorsed by the Intramural Division Directors. (a) Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Cancer Genetics Network, a national, prospective follow-up study of genetically at-risk women who elect to undergo risk-reducing salpingo-oophorectomy (RRSO) has been launched (Clinical Center Protocol #02-C-0268; GOG 0199). This is addressing such issues as: (a) what is the prevalence of clinically occult ovarian cancer at the time of risk-reducing surgery? (b) are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) what is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to this operation? and (d) how does this surgical procedure affect the quality of life and morbidity from non-oncologic medical conditions for the women who elect it? Women who elect to retain their ovaries are being screened with a novel ovarian cancer screening algorithm based on longitudinal changes of CA125 (and other tumor marker) levels over time. This study opened to accrual in the summer of 2003, and is presently accruing patients at 34 sites around the United States. We are in the midst of conducting a pilot study to assess the feasibility of harvesting ovarian surface epithelial cells from the ovaries that are removed to reduce the genetic risk of ovarian cancer in GOG 0199. We are evaluating whether these cells can be used for cytology, genomic and proteomic analyses. If the pilot demonstrates the feasibility of this strategy, the collection of these cells will be added to GOG 0199 on a limited institution basis. Early data are encouraging. (b) CGB's second invervention project is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer (Protocol 02-2-0009). This protocol is actively accruing patients. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics (Protocol 02-C-0008), and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis or risk stratification tool in this setting, and as a potential source of biological materials for molecular genetic studies. Several behavioral studies have been incorporated into the Breast Imaging protocol. These include: (1) a pilot study of a novel tool (the Colored EcoGenetic Relations Map) for documenting individual and family support networks as a guide to genetic counseling; and (2) an assessment of mutation-negative women who persist in following screening programs designed for high-risk women. (c) Our study of persons from families with one of a variety of inherited bone marrow failure syndromes (e.g., Fanconi's anemia) is now open to patient accrual (Clinical Center Protocol #02-C-0052). Among the non-hematologic malignancies which occur excessively in these individuals are squamous cell carcinomas of the oral cavity, esophagus, labia and cervix. Participants in this study are undergoing intensive evaluation in search of both clinical and molecular abnormalities which might represent cancer precursors, particularly with regard to cancers of the head/neck and female genitals. The role of the human papilloma virus (HPV) in the etiology of these cancers will be explored. If suitable clinical or molecular endpoints can be identified, consideration will be given to the development of an intervention program which would target persons from these high-risk families. (d) We are collaborating with colleagues in NCI's Center for Cancer Research by actively recruiting members of our hereditary breast/ovarian cancer families into CCR's newest breast cancer chemoprevention trial, a study of exemestane with or without celecoxib. (e) Plans to initiate a series of Phase II clinical trials (in collaboration with the University of Arizona Cancer Center) among patients with dysplastic nevi, a known melanoma precursor, to seek biologically active compounds which might hold promise as topical skin cancer chemoprevention agents is currently on hold, pending recruitment of additional staff. These studies have evolved from the Arizona Cancer Center's Skin Cancer Chemoprevention Program Project Grant. Candidate agents which would be studied include topical tretinoin (all-trans retinoic acid), 9-cis retinoic acid, diflouromethylornithine (DFMO), epigallotcatechin gallate, perillyl alcohol and sodium salicylate. A panel of surrogate endpoint biomarkers would be employed as indicators of biological activity. This project would represent a natural evolution of DCEG's long-standing interests in hereditary melanoma and melanoma precursors.